The key to azelaic acid lies in "how it's dissolved." A low-irritation serum formulation demonstrating acne-fighting efficacy comparable to a 20% cream has been established.

Key points of the research

• We have developed a formulation technology that dissolves poorly soluble azelaic acid (AZA) without neutralization, while taking irritation into consideration.
• In a 12-week clinical trial, a 3% AZA-containing dissolvable serum showed a similar reduction in total skin lesion count as a 20% AZA-containing dispersed cream.
• No side effects were found to be causally related to the test product during the trial period, and itching and irritation in the initial stages of use tended to be less with the AZA 3% dissolved serum.
• A 3% AZA dissolving serum has approximately four times the skin penetration efficiency of AZA compared to a 20% AZA dispersion cream.
• AZA 3% dissolving serum, like AZA 20% dispersion cream, has a high bactericidal effect against acne bacteria.

Research Background

Aiming to achieve both the "effectiveness" and "ease of use in daily life" of azelaic acid.

Azelaic acid (AZA) is recommended in guidelines1) as one of the treatment options for acne vulgaris, and has been reported to have keratinization normalizing effects, antibacterial effects, antioxidant effects, tyrosinase activity inhibitory effects, and anti-inflammatory effects.
AZA is a poorly soluble component that does not dissolve easily in either water or oil, making it difficult to dissolve and formulate at high concentrations. Therefore, conventional high-concentration AZA formulations have widely employed a method of "dispersing" AZA as fine particles in cream. Although the efficacy and safety of 20% AZA-containing creams for acne vulgaris in Japanese people have been confirmed, there was room for improvement in terms of ease of daily use in terms of irritation and feel.
Therefore, aiming to create a formulation that leverages the effectiveness of AZA while also considering irritation and user experience, we focused not simply on lowering the concentration, but on designing a formulation that brings out the characteristics of AZA even at low concentrations.

The key to making the most of AZA's characteristics is the "degree of neutralization."

AZAは弱酸性で、pH条件によって電離状態が変化します。殺菌作用は低pH条件で高くなることが報告されており2,3)、当社の検討でも、中和度が高くなるほど皮膚への浸透性が低下することを確認しました。一方、AZAは中和すると溶解しやすくなるため、中和せず溶解させることが技術的な課題でした。
そこで当社は、AZAを主として中和することなく製剤中に完全溶解させる技術を開発。低濃度でありながら皮膚への効率的な浸透特性や殺菌作用などの特性を生かし、刺激にも配慮したセラム製剤の実現に至りました。

Figure 2: Image of AZA formulation state and formulation characteristics

1) Guidelines for the Treatment of Acne Vulgaris and Rosacea 2023
2) Feng X et al: Clin Cosmet Investig Dermatol 17: 2359, 2024
3) Bojar RA, et al. J Antimicrob Chemother. 1994;34:321–330.

result

Result 1: Total number of skin lesions decreased after 12 weeks with AZA 3% dissolved serum.

A 12-week, rater-blinded, randomized, left-right comparative study was conducted in 28 individuals with mild to moderate acne vulgaris. Each participant received either AZA 20% dispersion cream or AZA 3% dissolving serum twice daily on one half of their face. The results showed that the AZA 3% dissolving serum reduced the total number of lesions to a level comparable to that of the AZA 20% dispersion cream. Furthermore, the AZA 3% dissolving serum reduced the number of lesions relatively early after the start of use, and showed a greater reduction in the percentage change in total lesions after 4 weeks compared to the AZA 20% dispersion cream.

Figure 3: Changes in the total number of skin lesions

Result 2: No side effects occurred, and there was a tendency for less itching and irritation in the initial stages of use.

During the 12-week trial period, no side effects were found to be causally related to the test product, and there were no cases of discontinuation or dropout. When subjects themselves evaluated itching and irritation after application, the number of subjects who reported "not feeling" any symptoms increased with longer use for both formulations. In particular, at the 2-week mark, the percentage of subjects who reported "not feeling itching" was 23.0 percentage points higher for the AZA 3% dissolving serum compared to the AZA 20% dispersion cream, and the percentage of subjects who reported "not feeling irritation" was 18.4 percentage points higher, indicating that the AZA 3% dissolving serum tended to cause less irritation in the initial stages of use. This technology suggests the possibility of utilizing the effectiveness of AZA while taking irritation into consideration.

Result 3: With the AZA 3% dissolved serum, the efficiency of AZA penetration into the skin was approximately four times higher.

We compared the skin penetration of a 20% AZA dispersion cream and a 3% AZA dissolving serum using human skin. 24 hours after application, the amount of AZA in the stratum corneum, epidermis/dermis, and receiver fluid was measured. The results showed that the proportion of AZA that migrated beyond the stratum corneum of the skin (stratum corneum, epidermis/dermis, and receiver fluid) was approximately four times higher for the 3% AZA dissolving serum compared to the 20% AZA dispersion cream.
This suggests that by dissolving AZA without neutralization, it may be possible to efficiently penetrate AZA into the skin even at low concentrations.

Result 4: High bactericidal effect against acne bacteria confirmed.

We evaluated the bactericidal activity against acne bacteria in a 3% AZA-dissolved serum and a 20% AZA-dispersed cream. The results showed that the 3% AZA-dissolved serum exhibited the same bactericidal effect as the 20% AZA-dispersed cream. This suggests that, despite the low concentration, incorporating AZA in a dissolved state allows the formulation to effectively utilize its properties.

Figure 5: Bactericidal activity of each formulation against acne bacteria

Future outlook

This study demonstrates the potential of a formulation technology that dissolves poorly soluble AZA without neutralization, while minimizing irritation, allowing AZA to efficiently penetrate the skin at low concentrations and exhibit its properties. Furthermore, in clinical trials involving individuals with mild to moderate acne vulgaris, the 3% AZA-dissolving serum reduced the number of skin lesions to a level comparable to the 20% AZA-dispersing cream, and fewer individuals experienced irritation during use. No side effects were found to be causally related to either test product.
Beyond the conventional approach of "containing AZA in high concentrations," we have discovered the possibility of a new formulation design that controls the state of the ingredient, improving penetration efficiency while reducing irritation. Moving forward, we will continue our research with the aim of developing formulations that are easy for customers to use on a daily basis while drawing out the inherent power of the ingredient itself.

Terminology

*1 Azelaic acid: A type of saturated dicarboxylic acid that also exists in nature. It has been reported to have keratinization normalizing effects, antibacterial effects, antioxidant effects, tyrosinase activity inhibitory effects, and anti-inflammatory effects. It is used overseas for acne and papular rosacea, and in Japan it is used as a cosmetic ingredient.

*3 Dispersed formulation: A formulation in which the ingredients are not dissolved but uniformly dispersed as fine particles within the formulation. The cream containing 20% azelaic acid used as a control in this study is an example of this dispersed formulation.

*4 Dissolving formulation: A formulation in which the active ingredient is dissolved within the formulation. In the 3% azelaic acid serum used in this study, the azelaic acid is included in a dissolved state without being neutralized.

*5 *Propionibacterium acnes* (C. acnes): One of the commensal bacteria present on the skin, known to be associated with acne vulgaris.